bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–07–14
eleven papers selected by
Xiao Qin, University of Oxford
  1. Mapping the chromatin accessibility landscape of zebrafish embryogenesis at single-cell resolution by SPATAC-seq.
  2. Advancing sequencing-based spatial transcriptomics with a comprehensive benchmarking study.
  3. A single-cell atlas of chromatin accessibility in mouse organogenesis.
  4. Cellular adaptation to cancer therapy along a resistance continuum.
  5. TFscope: systematic analysis of the sequence features involved in the binding preferences of transcription factors.
  6. Panpipes: a pipeline for multiomic single-cell and spatial transcriptomic data analysis.
  7. A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer.
  8. Activation of fetal-like molecular programs during regeneration in the intestine and beyond.
  9. In-depth organoid profiling of pancreatic cancer.
  10. Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer.
  11. Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.
  1. Nat Cell Biol. 2024 Jul 08.
    Mapping the chromatin accessibility landscape of zebrafish embryogenesis at single-cell resolution by SPATAC-seq.
    Keyong Sun, Xin Liu, Runda Xu, Chang Liu, Anming Meng, Xun Lan.
      Currently, the dynamic accessible elements that determine regulatory programs responsible for the unique identity and function of each cell type during zebrafish embryogenesis lack detailed study. Here we present SPATAC-seq: a split-pool ligation-based assay for transposase-accessible chromatin using sequencing. Using SPATAC-seq, we profiled chromatin accessibility in more than 800,000 individual nuclei across 20 developmental stages spanning the sphere stage to the early larval protruding mouth stage. Using this chromatin accessibility map, we identified 604 cell states and inferred their developmental relationships. We also identified 959,040 candidate cis-regulatory elements (cCREs) and delineated development-specific cCREs, as well as transcription factors defining diverse cell identities. Importantly, enhancer reporter assays confirmed that the majority of tested cCREs exhibited robust enhanced green fluorescent protein expression in restricted cell types or tissues. Finally, we explored gene regulatory programs that drive pigment and notochord cell differentiation. Our work provides a valuable open resource for exploring driver regulators of cell fate decisions in zebrafish embryogenesis.
    DOI:  https://doi.org/10.1038/s41556-024-01449-0
  2. Nat Methods. 2024 Jul 08.
    Advancing sequencing-based spatial transcriptomics with a comprehensive benchmarking study.
      
    DOI:  https://doi.org/10.1038/s41592-024-02326-2
  3. Nat Cell Biol. 2024 Jul 08.
    A single-cell atlas of chromatin accessibility in mouse organogenesis.
    Keyong Sun, Xin Liu, Xun Lan.
      Organogenesis is a highly complex and precisely regulated process. Here we profiled the chromatin accessibility in >350,000 cells derived from 13 mouse embryos at four developmental stages from embryonic day (E) 10.5 to E13.5 by SPATAC-seq in a single experiment. The resulting atlas revealed the status of 830,873 candidate cis-regulatory elements in 43 major cell types. By integrating the chromatin accessibility atlas with the previous transcriptomic dataset, we characterized cis-regulatory sequences and transcription factors associated with cell fate commitment, such as Nr5a2 in the development of gastrointestinal tract, which was preliminarily supported by the in vivo experiment in zebrafish. Finally, we integrated this atlas with the previous single-cell chromatin accessibility dataset from 13 adult mouse tissues to delineate the developmental stage-specific gene regulatory programmes within and across different cell types and identify potential molecular switches throughout lineage development. This comprehensive dataset provides a foundation for exploring transcriptional regulation in organogenesis.
    DOI:  https://doi.org/10.1038/s41556-024-01435-6
  4. Nature. 2024 Jul 10.
    Cellular adaptation to cancer therapy along a resistance continuum.
    Gustavo S França, Maayan Baron, Benjamin R King, Jozef P Bossowski, Alicia Bjornberg, Maayan Pour, Anjali Rao, Ayushi S Patel, Selim Misirlioglu, Dalia Barkley, Kwan Ho Tang, Igor Dolgalev, Deborah A Liberman, Gal Avital, Felicia Kuperwaser, Marta Chiodin, Douglas A Levine, Thales Papagiannakopoulos, Andriy Marusyk, Timothée Lionnet, Itai Yanai.
      Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance1. In addition to genetic mutations2, recent research has identified a role for non-genetic plasticity in transient drug tolerance3 and the acquisition of stable resistance4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.
    DOI:  https://doi.org/10.1038/s41586-024-07690-9
  5. Genome Biol. 2024 Jul 10. 25(1): 187
    TFscope: systematic analysis of the sequence features involved in the binding preferences of transcription factors.
    Raphaël Romero, Christophe Menichelli, Christophe Vroland, Jean-Michel Marin, Sophie Lèbre, Charles-Henri Lecellier, Laurent Bréhélin.
      Characterizing the binding preferences of transcription factors (TFs) in different cell types and conditions is key to understand how they orchestrate gene expression. Here, we develop TFscope, a machine learning approach that identifies sequence features explaining the binding differences observed between two ChIP-seq experiments targeting either the same TF in two conditions or two TFs with similar motifs (paralogous TFs). TFscope systematically investigates differences in the core motif, nucleotide environment and co-factor motifs, and provides the contribution of each key feature in the two experiments. TFscope was applied to > 305 ChIP-seq pairs, and several examples are discussed.
    DOI:  https://doi.org/10.1186/s13059-024-03321-8
  6. Genome Biol. 2024 Jul 08. 25(1): 181
    Panpipes: a pipeline for multiomic single-cell and spatial transcriptomic data analysis.
    Fabiola Curion, Charlotte Rich-Griffin, Devika Agarwal, Sarah Ouologuem, Kevin Rue-Albrecht, Lilly May, Giulia E L Garcia, Lukas Heumos, Tom Thomas, Wojciech Lason, David Sims, Fabian J Theis, Calliope A Dendrou.
      Single-cell multiomic analysis of the epigenome, transcriptome, and proteome allows for comprehensive characterization of the molecular circuitry that underpins cell identity and state. However, the holistic interpretation of such datasets presents a challenge given a paucity of approaches for systematic, joint evaluation of different modalities. Here, we present Panpipes, a set of computational workflows designed to automate multimodal single-cell and spatial transcriptomic analyses by incorporating widely-used Python-based tools to perform quality control, preprocessing, integration, clustering, and reference mapping at scale. Panpipes allows reliable and customizable analysis and evaluation of individual and integrated modalities, thereby empowering decision-making before downstream investigations.
    DOI:  https://doi.org/10.1186/s13059-024-03322-7
  7. Cancer Discov. 2024 Jul 08.
    A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer.
    Anupriya Singhal, Hannah C Styers, Jonathan Rub, Zhuxuan Li, Stefan R Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela.
      Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage-tracing identifies these enriched classical PDAC cells to be a reservoir for disease relapse. Genetic ablation of the classical cell-state is synergistic with KRAS inhibition, providing a pre-clinical proof-of-concept for this therapeutic strategy. Our findings motivate combining classical-state directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0740
  8. Cell Stem Cell. 2024 Jul 05. pii: S1934-5909(24)00186-3. [Epub ahead of print]31(7): 949-960
    Activation of fetal-like molecular programs during regeneration in the intestine and beyond.
    Sara Viragova, Dong Li, Ophir D Klein.
      Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.
    Keywords:  Hippo; YAP; colon; dedifferentiation; developmental reprogramming; epithelium; fetal-like reversion; intestinal epithelium; intestine; liver; paligenosis; plasticity; regeneration; stem cells; stomach
    DOI:  https://doi.org/10.1016/j.stem.2024.05.009
  9. Nat Rev Cancer. 2024 Jul 09.
    In-depth organoid profiling of pancreatic cancer.
    Ju Eun Maeng, Ja-Lok Ku.
      
    DOI:  https://doi.org/10.1038/s41568-024-00726-2
  10. Cancer Cell. 2024 Jul 08. pii: S1535-6108(24)00234-4. [Epub ahead of print]42(7): 1268-1285.e7
    Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer.
    Yuqing Chen, Dongfang Wang, Yingjie Li, Lu Qi, Wen Si, Yufei Bo, Xueyan Chen, Zhaochen Ye, Hongtao Fan, Baolin Liu, Chang Liu, Li Zhang, Xiaoyan Zhang, Zhongwu Li, Linna Zhu, Aiwen Wu, Zemin Zhang.
      Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.
    Keywords:  eoadjuvant immunotherapy; sequential multi-model single-cell sequencing; systemic immunity
    DOI:  https://doi.org/10.1016/j.ccell.2024.06.009
  11. Cancers (Basel). 2024 Jun 27. pii: 2354. [Epub ahead of print]16(13):
    Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.
    Oleksii S Rukhlenko, Hiroaki Imoto, Ayush Tambde, Amy McGillycuddy, Philipp Junk, Anna Tuliakova, Walter Kolch, Boris N Kholodenko.
      Understanding signaling patterns of transformation and controlling cell phenotypes is a challenge of current biology. Here we applied a cell State Transition Assessment and Regulation (cSTAR) approach to a perturbation dataset of single cell phosphoproteomic patterns of multiple breast cancer (BC) and normal breast tissue-derived cell lines. Following a separation of luminal, basal, and normal cell states, we identified signaling nodes within core control networks, delineated causal connections, and determined the primary drivers underlying oncogenic transformation and transitions across distinct BC subtypes. Whereas cell lines within the same BC subtype have different mutational and expression profiles, the architecture of the core network was similar for all luminal BC cells, and mTOR was a main oncogenic driver. In contrast, core networks of basal BC were heterogeneous and segregated into roughly four major subclasses with distinct oncogenic and BC subtype drivers. Likewise, normal breast tissue cells were separated into two different subclasses. Based on the data and quantified network topologies, we derived mechanistic cSTAR models that serve as digital cell twins and allow the deliberate control of cell movements within a Waddington landscape across different cell states. These cSTAR models suggested strategies of normalizing phosphorylation networks of BC cell lines using small molecule inhibitors.
    Keywords:  breast cancer; cSTAR; digital twins; machine learning; mathematical modeling; network reconstruction; signaling networks
    DOI:  https://doi.org/10.3390/cancers16132354
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